The goal of this project is to identify therapeutics that accelerate the recovery from acute organ failure. Cell injury and death induced by ischemia/reperfusion (I/R), drugs, toxicants, and trauma lead to failure of many organs, including the kidney. Mitochondrial dysfunction is a common consequence of these insults and a major mechanism of cell injury and death. The majority of research in the field of acute kidney injury (AKI) has focused on the events that initiate renal dysfunction, but therapeutic agents are lacking. This suggests that more successful therapies require the examination of new targets and a focus on accelerating recovery from AKI. We recently determined that mice subjected to bilateral renal I/R induced AKI and rats subjected to myoglobinuric AKI had elevated serum creatinine 24 h after injury which partially recovered over six days post- injury. Mitochondrial electron transport chain and ATP synthesis proteins were depleted 24 h after injury and did not recover over six days, revealing persistent disruption of mitochondrial function after AKI. Consequently, we propose that therapeutics that increase mitochondrial biogenesis (MB) will promote recovery from AKI. As part of our drug discovery program to identify drugs that induce MB we identified formoterol, a specific long- acting b2-adrenergic receptor agonist (b2-AR), was a potent and efficacious inducer of MB in renal proximal tubular cells (RPTC). Formoterol is a FDA-approved drug used to treat asthma. Additional studies revealed that formoterol induced MB in the kidneys of mice at a low dose. However, the signaling pathway(s) responsible for formoterol-induced MB has not been elucidated. Finally, preliminary studies demonstrated that mice treated with formoterol 24 h after I/R, when renal dysfunction is established, accelerated recovery of [mitochondrial and] renal function. We hypothesize that formoterol induces MB through the b2-AR and that formoterol accelerates recovery of [mitochondrial and] renal function following I/R in mice. To address this hypothesis we propose the following Specific Aims: 1) Elucidate the signaling pathway(s) of formoterol- induced MB in RPTC [and following oxidant injury in RPTC], 2) Determine efficacy, potency and mechanism of formoterol-induced MB in mice, and 3) Elucidate the effects of formoterol on the recovery of mitochondrial and renal function following renal I/R-induced AKI in vivo. Successful completion of these experiments will advance the field by 1) identifying the precise signaling pathway that induces MB through b2-AR, 2) demonstrating that stimulating the recovery of mitochondrial function results in the acceleration of recovery of renal function, and 3) providing a rapidly clinically translatable treatment for AKI.